Vascular cholesterol inhibitors and use thereof

Abstract

The present invention relates to compounds having pharmacological activity in the treatment of vascular cholesterol accumulation, plasma low-density lipoproteins (LDL) abnormal aggregation and/or inhibition or reduction of the formation of VSMC foam cells, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy and/or prophylaxis of conditions wherein decrease of vascular cholesterol accumulation, inhibition of LDL aggregation, inhibition or reduction of the formation of VSMC foam cells and/or prevention of aggregated LDL (agLDL) internalization is useful such as atherosclerosis, coronary artery disease, stroke, peripheral artery disease, angina pectoris, thrombosis, hyperlipidemia, hyperlipoproteinemia type II, familial hypercholesterolemia, familial combined hyperlipidemia, type II diabetes, hypothyroidism, Cushing's syndrome and obesity.

1 . A compound of formula (I):
   R 1 -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -D-Glu-D-Asp-AA 6 -AA 7 -AA 8 -D-Glu-D-Glu-AA 9 -NH 2    (I)
   wherein
 R 1  is a C24 acyl group, 
 AA 1  is either absent or is Gly 
 AA 2  is either absent or is D-Asp 
 AA 3  is either absent or is D-Asn 
 AA 4  is either absent or is D-Asp 
 AA 5  is selected from the group consisting of D-Ser and D-Ala 
 AA 6  is selected from the group consisting of D-Asn and D-Gln 
 AA 7  is selected from the group consisting of D-Ala, D-Arg, D-Lys and D-Ser 
 AA 8  is selected from the group consisting of D-Asp and D-Glu 
 AA 9  is selected from the group consisting of D-Ala, D-Arg, D-Asn, D-Gln, D-Leu and D-Trp or a salt or solvate thereof. 
   
     
     
         2 . The compound according to  claim 1  wherein R 1  is acetyl. 
     
     
         3 . The compound according to  claim 1  wherein AA 1  is absent. 
     
     
         4 . The compound according to  claim 1  wherein AA 2  is absent. 
     
     
         5 . The compound according to  claim 1  wherein AA 3  is absent. 
     
     
         6 . The compound according to  claim 1  wherein -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 - is either absent or is selected from the group consisting of -Gly-D-Asp-D-Asn-D-Asp-D-Ser, -D-Asp-D-Asn-D-Asp-D-Ser- and -D-Asn-D-Asp-D-Ser-, -D-Asp-D-Ser and -D-Asp-D-Ala-. 
     
     
         7 . The compound according to  claim 1  wherein AA 5  is D-Ser. 
     
     
         8 . The compound according to  claim 1  wherein -AA 6 -AA 7 -AA 8 - is selected from the group consisting of -D-Asn-D-Ser-D-Asp-, -D-Asn-D-Ala-D-Asp-, -D-Gln-D-Ser-D-Glu-, -D-Gln-D-Ala-D-Glu-, -D-Asn-D-Arg-D-Asp- and -D-Asn-D-Lys-D-Asp-. 
     
     
         9 . The compound according to  claim 8  wherein -AA 6 -AA 7 -AA 8 - is -D-Asn-D-Ser-D-Asp-. 
     
     
         10 . The compound according to  claim 1  wherein -AA 9 - is selected from the group consisting of D-Ala and D-Asn. 
     
     
         11 . The compound according to  claim 1  selected from the group consisting of:
 Ac-Gly-D-Asp-D-Asn-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Ala-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Gln-D-Ser-D-Glu-D-Glu-D-Glu-D-Gln-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Gln-D-Ala-D-Glu-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Arg-D-Asp-D-Glu-D-Glu-D-Arg-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Arg-D-Asp-D-Glu-D-Glu-D-Leu-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Arg-D-Asp-D-Glu-D-Glu-D-Trp-NH 2    
 Ac-D-Ser-D-Glu-D-Asp-D-Asn-D-Lys-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Asp-D-Asn-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Asn-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Asp-D-Asn-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Asn-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ser-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Ala-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Asp-D-Ala-D-Glu-D-Asp-D-Asn-D-Ala-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 Ac-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Lys-D-Asp-D-Glu-D-Glu-D-Asn-NH 2    
 Ac-D-Asp-D-Ser-D-Glu-D-Asp-D-Asn-D-Lys-D-Asp-D-Glu-D-Glu-D-Ala-NH 2    
 
       and a pharmaceutically acceptable salt or solvate thereof. 
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         13 .- 17 . (canceled) 
     
     
         18 . A method for the prevention and/or treatment of conditions wherein decrease of vascular cholesterol accumulation, inhibition of LDL aggregation; prevention of aggregated LDL (agLDL) internalization and/or inhibition or reduction of the formation of VSMC foam cells is useful in a subject in need thereof comprising the administration of a compound according to  claim 1 . 
     
     
         19 . A method according to  claim 18  wherein the condition is selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral artery disease, angina pectoris, thrombosis, hyperlipidemia, hyperlipoproteinemia type II, familial hypercholesterolemia, familial combined hyperlipidemia, type II diabetes, hypothyroidism, Cushing's syndrome and obesity.